An Efficient Synthesis of Oxygen-Bridged Spirooxindoles via Microwave-Promoted Multicomponent Reaction

A microwave-promoted multicomponent reaction of isatins, α-amino acids and 1,4-dihydro-1,4-epoxynaphthalene is achieved under environmentally friendly conditions, delivering oxygen-bridged spirooxindoles within 15 min in good to excellent yields. The attractive features of the 1,3-dipolar cycloaddition are the compatibility of various primary amino acids and the high efficiency of the short reaction time. Moreover, the scale-up reaction and synthetic transformations of spiropyrrolidine oxindole further demonstrate its synthetic utility. This work provides powerful means to expand the structural diversity of spirooxindole as a promising scaffold for novel drug discovery.


Introduction
Green chemistry is essential to contribute to sustainability, it minimizes the energy requirements, reagent consumption, as well as the generation of wastes [1][2][3]. Microwave technology is in line with the category of green chemistry, since the first reports in the 1980s, microwave technology has proven to be a valuable tool for synthetic organic chemistry [4][5][6][7][8].
Reactions can be completed in minutes usually, and both product yields and selectivity can often be enhanced over conventional approaches. Compared with traditional thermal conditions (oil bath or a heating block), the distinctive features of microwave-assisted reactions include superior reaction efficiency, environmentally benign reaction condition, better control of the reaction process, and its capability to rapidly screen a wide range of experimental parameters. Based on the above characteristics, microwave technology provides a more convenient and ingenious alternative for green synthesis of high-value chemicals.
Multicomponent reactions (MCRs) represent one of the most powerful reactions leading to structurally diverse molecules, which allow the creation of several chemical bonds from simple starting material in one pot [9][10][11][12][13]. The remarkable advantages of multicomponent reactions include high bond-forming efficiency, operational simplicity and superior atom economy, making them convenient over the stepwise methods. Among the various N-heterocycles, spirooxindoles are featured widely in a variety of pharmacologically active substances [14,15], which is of great interest to synthetic chemists. [16][17][18][19][20][21][22][23][24]. As one of the most attractive subtypes, spiropyrrolidine oxindoles often exhibit intriguing biological activities [25]. Multicomponent reactions provide key opportunities for the construction of spiropyrrolidine oxindoles, and significant efforts have been made toward the designing of novel and practical strategies to access this important class of compounds [26][27][28][29][30][31].
We notice that oxabicyclic alkenes show potentially interesting reactivities owing to the inherent strain, and they have been widely employed in both ring-retentive and ring-opening catalytic transformations, including dimerization [32], cycloaddition [33][34][35], ring-opening/rearrangement reaction [36], hydrofunctionalization [37][38][39][40], and C−H activation [41,42]. Though great success has been achieved in traditional 1,3-dipolar cycloaddition of azomethine ylides prepared from isatins and α-amino acids with various electron-Molecules 2023, 28, 3508 2 of 17 deficient alkenes as dienophiles, the strained oxabicyclic alkenes are scarcely involved. To the best of our knowledge, there is only an elegant work disclosed by Parthasarathy and co-workers (Scheme 1a). They explored 1,3-dipolar cycloaddition of azomethine ylides with heterobicyclic alkenes at 80 • C for 6 h [43]. Despite considerable progress, it cannot be ignored that it remains a few challenges in the current method. One is the limited amino acids substrate scope, as the reported work focuses on sarcosine and proline. Moreover, the required reaction time often lasts for hours. Therefore, the synthesis of oxygen-bridged spirooxindoles in several minutes with diverse primary amino acids as substrates is quite challenging and not established. With these problems in mind, and in continuation of our interest in the 1,3-dipolar cycloaddition (Scheme 1b) [44], we wish to offer a microwavepromoted multicomponent reaction for the synthesis of oxygen-bridged spirooxindoles in a very short time with diverse primary amino acids as reaction partners (Scheme 1c).
We notice that oxabicyclic alkenes show potentially interesting reactivities owing to the inherent strain, and they have been widely employed in both ring-retentive and ringopening catalytic transformations, including dimerization [32], cycloaddition [33][34][35], ring-opening/rearrangement reaction [36], hydrofunctionalization [37][38][39][40], and C−H activation [41,42]. Though great success has been achieved in traditional 1,3-dipolar cycloaddition of azomethine ylides prepared from isatins and α-amino acids with various electron-deficient alkenes as dienophiles, the strained oxabicyclic alkenes are scarcely involved. To the best of our knowledge, there is only an elegant work disclosed by Parthasarathy and co-workers (Scheme 1a). They explored 1,3-dipolar cycloaddition of azomethine ylides with heterobicyclic alkenes at 80 °C for 6 h [43]. Despite considerable progress, it cannot be ignored that it remains a few challenges in the current method. One is the limited amino acids substrate scope, as the reported work focuses on sarcosine and proline. Moreover, the required reaction time often lasts for hours. Therefore, the synthesis of oxygen-bridged spirooxindoles in several minutes with diverse primary amino acids as substrates is quite challenging and not established. With these problems in mind, and in continuation of our interest in the 1,3-dipolar cycloaddition (Scheme 1b) [44], we wish to offer a microwave-promoted multicomponent reaction for the synthesis of oxygen-bridged spirooxindoles in a very short time with diverse primary amino acids as reaction partners (Scheme 1c). Scheme 1. (a) Previous work of 1,3-dipolar cycloaddition of isatins, α-amino acids and oxabicyclic alkenes, (b) Our previous work of 1,3-dipolar cycloaddition, and (c) Microwave-promoted multicomponent reaction with diverse primary amino acids as reaction partner (This Work).

Results and Discussion
We commenced our investigation with isatin 1a, proline 2a and 1,4-dihydro-1,4epoxynaphthalene 3a as model substrates. To our delight, microwave irradiation can promote the desired annulation reaction under catalyst-or additive-free conditions. Treatment of 1a, 2a and 3a in THF at 70 • C for 15 min, the desired corresponding [3+2] annulation product 4a was obtained as a single diastereomer in 40% yield (Table 1, entry 1). Encouraged by the initial result, we then focused on solvent screening; typical polar and nonpolar solvents were tested for the reaction. Generally, the results revealed that the solvents have a great influence on the reaction outcome, and alcohols are better than other solvents (Table 1, entries 2-8). Notably, MeOH gave the optimal results (73% yield, Table 1, entry 5). Further extensive studies regarding the temperature were conducted; however, improving or lowering the temperature was not beneficial to the reaction outcome (entries 9-11). A further increase in the reaction time (20, 25 or 30 min) did not significantly improve the reaction yield (entries [12][13][14], and a shorter time (10 min) indicated a negative effect on the result of the reaction (entry 15). Finally, the yield could be improved to 83% by switching the equivalent of reactants (entries [16][17]. Encouraged by the initial result, we then focused on solvent screening; typical pol nonpolar solvents were tested for the reaction. Generally, the results revealed that t vents have a great influence on the reaction outcome, and alcohols are better than solvents (Table 1, entries 2-8). Notably, MeOH gave the optimal results (73% yield, 1, entry 5). Further extensive studies regarding the temperature were conducted; how improving or lowering the temperature was not beneficial to the reaction outcome (e 9-11). A further increase in the reaction time (20, 25 or 30 min) did not significant prove the reaction yield (entries [12][13][14], and a shorter time (10 min) indicated a ne effect on the result of the reaction (entry 15). Finally, the yield could be improved t by switching the equivalent of reactants (entries [16][17]. With the optimal conditions in hand, we explored the substrates' scope of isatin the results were summarized in Scheme 2. Generally, isatins with various substit were suitable to the reaction condition. When 4-bromoisatin was subjected to the pole cycloaddition, product 4b was obtained in 33% yield. We speculated that the reaction activity was attributed to a large steric hindrance group nearby the reactiv ter. Isatins equipped with electron-donating (methyl) or electron-withdrawing (fluoro, chloride, bromide, nitro) at the C5 position of the benzene ring were well-tol for the cycloaddition, affording the desired adducts in good to excellent yields (4c-4 89% yields). Meanwhile, 6-methoxy-isatin participated in the three-component re smoothly, and 4h was separated in 88% yield. When the substitution of bromide w away from the active center, there was no obvious influence on the reaction resul yield of 4i). Next, isatins with the N-protection group were explored, and the ou showed that alkyl and phenyl groups were friendly to this reaction, giving 4j and With the optimal conditions in hand, we explored the substrates' scope of isatins, and the results were summarized in Scheme 2. Generally, isatins with various substitutions were suitable to the reaction condition. When 4-bromoisatin was subjected to the 1,3dipole cycloaddition, product 4b was obtained in 33% yield. We speculated that the lower reaction activity was attributed to a large steric hindrance group nearby the reactive center. Isatins equipped with electron-donating (methyl) or electron-withdrawing group (fluoro, chloride, bromide, nitro) at the C5 position of the benzene ring were well-tolerated for the cycloaddition, affording the desired adducts in good to excellent yields (4c-4g, 72-89% yields). Meanwhile, 6-methoxy-isatin participated in the three-component reaction smoothly, and 4h was separated in 88% yield. When the substitution of bromide was far away from the active center, there was no obvious influence on the reaction result (87% yield of 4i). Next, isatins with the N-protection group were explored, and the outcome showed that alkyl and phenyl groups were friendly to this reaction, giving 4j and 4k in 94% and 91% yields, respectively. However, N-acetyl protected isatin furnished only trace products. Furthermore, other diketones and their analogs such as acenaphthequinone and ninhydrin were also found to be effective, as demonstrated in the successful installation of 4m and 4n. However, other diketones including 9,10-phenanthrenequinone, 1,2-diphenyl ethanedione, cyclohexanedione, acetylacetone, ethyl pyruvate and ethyl 3,3,3-trifluoropyruvate failed to undergo this reaction under standard conditions. Next, to examine the feasibility of this reaction, we examined the variation of the amino acid component toward the formation of oxygen-bridged spirooxindoles (Scheme 3). Initially, the natural L-alanine was found to be unfruitful for the optimal condition, and no desired product could be isolated from the reaction mixture. We speculated that the side reactions of azomethine ylides from isatin and L-alanine are largely preferred over [3+2] cycloadditions with a dipolarophile, which makes this reaction particularly challenging. Gratefully, we found that the L-phenylalanine proceeded smoothly in methanol−water medium (MeOH:H 2 O = 3:1), but changing the solvent still had no positive effect on alanine. Under similar conditions, the present cycloaddition reaction was also successfully extended to other primary α-amino acids with side chains, thus greatly expanding the types of spirooxindoles accessible using this method. 4-Iodo-L-phenylalanine and L-tyrosine led to the 5b and 5c in 57% and 21% yields, respectively. It is worth noting that N-methyl protection is necessary for 5c, otherwise, no expected product was observed in the reaction system. As a common intermediate in about 20 new antihypertensive drugs in the world, L-homophenylalanine showed quite promising reactivities, leading to the desired product 5d in moderate yield. The three-component reaction of isatin with L-methionine, L-lysine and L-leucine with 3a resulted in the expected products in 73-80% yields as single isomers. It was found that the L-isoleucine afforded the spirooxindoles 5h as chromatographically separable diastereomers (1.7:1 dr). The use of tryptophan as a reaction partner proved to have low efficiency, delivering the corresponding product 5i in only trace yield. It was hypothesized that in the presence of unprotected amino acid residues, the side reactions were preferred over the expected cyclization reaction. Next, L-thiproline was tested, and 5j was obtained with a 78% yield. The structure and relative stereochemistry of 5j was unambiguously established by Single-crystal X-ray analysis (CCDC: 2243483). When trans-4-cyclohexyl-L-proline was selected for the cycloaddition, the two diastereomers of 5k were isolated in almost the same yield (46% vs. 42%). In contrast, the utilization of Lpiperidine-2-carboxylic acid, L-serine and peptide L-Ala-L-Ala-OH proved unsuccessful for the reaction conditions.
Based on the experimental results and the reported literature [45], possible mechanisms for cycloaddition were proposed as shown in Scheme 4. First, the condensation of isatin 1a with proline 2a, followed by decarboxylation furnishes ylide intermediate A, which reacts as a 1,3-dipole with 3a through two possible pathways A and B. Path A leads to the formation of the thermodynamically more stable endo-cycloadduct 4a, whereas affording the exo-cycloadduct 4a' through path B is probably disfavored.
To explore the synthetic utility of this established protocol, we investigated the one-pot three-component [3+2] cycloaddition cascade on a gram scale, affording the corresponding 6 in synthetically useful yield (61%) with excellent diastereoselectivity (Sheme 5). To further illustrate the synthetic values of this three-component reaction, the derivatizations of the gram reaction product were carried out (Scheme 5). First, in the presence of TfOH, compound 6 was successfully transformed into product 7 by deoxyaromatization. Then, 6 was treated with (Boc) 2 O/DMAP, affording N-Boc substituted spirooxindole 8 in good yield. Next, by reduction of 6 with LiAlH 4 in diethyl ether at ambient temperature, 2hydroxyindoline 9 was obtained as a single diastereomer in 64% yield. These representative examples highlight the advantages and potential application of this method. Based on the experimental results and the reported literature [45], possible mechanisms for cycloaddition were proposed as shown in Scheme 4. First, the condensation of isatin 1a with proline 2a, followed by decarboxylation furnishes ylide intermediate A, which reacts as a 1,3-dipole with 3a through two possible pathways A and B. Path A leads to the formation of the thermodynamically more stable endo-cycloadduct 4a, whereas affording the exo-cycloadduct 4a' through path B is probably disfavored. To explore the synthetic utility of this established protocol, we investigated the onepot three-component [3+2] cycloaddition cascade on a gram scale, affording the corresponding 6 in synthetically useful yield (61%) with excellent diastereoselectivity (Sheme 5). To further illustrate the synthetic values of this three-component reaction, the derivatizations of the gram reaction product were carried out (Scheme 5). First, in the presence of TfOH, compound 6 was successfully transformed into product 7 by deoxyaromatization. Then, 6 was treated with (Boc)2O/DMAP, affording N-Boc substituted spirooxindole 8 in good yield. Next, by reduction of 6 with LiAlH4 in diethyl ether at ambient temperature, 2-hydroxyindoline 9 was obtained as a single diastereomer in 64% yield. These representative examples highlight the advantages and potential application of this method.

General Information
All starting materials were purchased from commercial suppliers and used without further purification unless otherwise stated. Thin-layer chromatography (TLC) was conducted with 0.25 mm Tsingdao silica gel plates (60F-254) and visualized by exposure to UV light (254 nm). Flash column chromatography was performed on Tsingdao silica gel (200-300 mesh) and neutral/basic aluminum oxide (200-300 mesh). 1 H NMR spectra were recorded with Bruker spectrometers (400 or 500 MHz) and reported relative to deuterated solvent signals or tetramethylsilane internal standard signals (see Supplementary Materials). Data for 1 H NMR spectra were reported as follows: chemical shift (δ/ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad), coupling constant (J/Hz) and integration. 13 C NMR spectra were recorded with Bruker spectrometers (125 MHz). Data for 13 C NMR spectra were reported in terms of chemical shift. 19 F NMR spectra were recorded with Bruker spectrometers (470 MHz). High-resolution mass spectrometry (HRMS) was conducted with a Bruker Apex IV RTMS. All microwave reactions were conducted in sealed glass vials with a microwave reactor, Discover SP from CEM Corp.  13 69 (m, 1H). 13     The cycloaddition product 6 (44 mg, 0.1 mmol), DMAP (2.4 mg, 0.02 mmol) and THF were added to a 25 mL sealed tube at 0 • C. Later, the mixture of (Boc) 2 O (0.12 mmol) and THF (1 mL) was added to the system dropwise. Then, the reaction mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction mixture was diluted with 10.0 mL of EtOAc and filtered through a plug of Celite, followed by washing with 2 mL of H 2 O three times, and the organic phase was dried with anhydrous sodium sulfate and filtered, and the solvent was removed under reduced pressure to give the crude product, which was purified by column chromatography on silica gel.

General Procedure for the Reduction of Cycloadduct 6 with Lithium Aluminum Hydride
To a solution of LiAlH 4 (43 mg, 1.1 mmol) in anhydrous diethyl ether (2 mL) under an argon atmosphere was added cycloadduct 6 (50 mg, 0.11 mmol), and the reaction mixture was stirred at room temperature for 4 h. After that, the mixture was cooled to 0 • C and 0.5 mL of H 2 O was added to this mixture. Then, 0.5 mL of a 10% NaOH solution and 0.5 mL of another portion of H 2 O were added to it. The reaction mixture was stirred for 5 min at ambient temperature. The organic layer was separated, and the aqueous phase was extracted with EtOAc (3 × 5 mL). The total organic mixture was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel.
The results of the X-ray diffraction analysis for compound 5j were deposited with the Cambridge Crystallographic Data Centre (CCDC 2243483).

Conclusions
Microwave-promoted multicomponent reactions of isatins, α-amino acids and 1,4dihydro-1,4-epoxynaphthalene have been demonstrated. Under environmentally friendly conditions, a variety of oxygen-bridged spirooxindoles were delivered in good to excellent yields within 15 min. This cascade protocol shows excellent diastereoselectivity and remarkable functional group tolerance, and a diversity of amino acids can be involved in this transformation. This work provides a powerful means to expand the structural diversity of spirooxindole as a promising scaffold for novel drug discovery.